Controlled release membranes have been used as a component of drug delivery system in wound dressings. Such membranes are by design permeable to drugs and are capable of controlling the rate at which the drugs are released from the membranes into the wound of a patient. Typically, the membrane is attached to an impermeable backing material by a pressure sensitive adhesive applied over the backing material, or a portion thereof, to attach the composite drug delivery system to the skin of the patient. The exposed surface of the pressure sensitive adhesive is generally covered by a release liner which is removed and discarded when the device is used.
Drugs or medications are defined herein as any biologically-active chemical or natural substance useful for treating a medical or veterinary disorder, or regulating the physiology of a human being or animal. Depending upon the type of drug or medication and the desired release rate, the controlled release membrane has heretofore been a layer of non-porous material such as ethylene vinyl acetate copolymer or crosslinked silicone rubber or a porous polymer-based film. Among the polymer systems selected for this purpose have been the hydrogels. Hydrogels can be defined as polymeric materials which in contact with water can swell but not dissolve due to chemical or physical crosslinkage of the polymer chains.
Typically, hydrogels are formed by polymerizing a hydrophilic monomer in an aqueous solution under conditions such that the prepolymer becomes crosslinked, forming a three-dimensional polymeric network which gels the solution. An example of a crosslinked polymer material derived from polyfunctional prepolymers are the polyurethanes. Polyurethane hydrogels are formed by polymerization of isocyanate-end capped prepolymers to create urea and urethane linkages. Drugs can be physically incorporated into the hydrogel by impregnation of the dried gel with aqueous or organic solutions containing the desired drug.
Representative examples of previously disclosed polyurethane hydrogels include the following: U.S. Pat. No. 4,241,537 (Wood) discloses a plant growth media comprising a hydrophilic polyurethane gel composition prepared from chain-extended polyols; random copolymerization is preferred with up to 50% propylene oxide units so that the prepolymer will be a liquid at room temperature. U.S. Pat. No. 3,939,123 (Matthews) discloses lightly crosslinked polyurethane polymers of isocyanate terminated prepolymers comprised of poly(ethyleneoxy) glycols with up to 35% of a poly(propyleneoxy) glycol or a poly(butyleneoxy) glycol. In producing the Matthews prepolymer, it is taught that the ratio of isocyanato groups to hydroxyl is from about 1.2 to 1.6 equivalents of isocyanato per equivalent of hydroxyl. A solids content of 25 to 40 wt. % is employed in forming the hydrogel. U.S. Pat. No. 4,118,354 (Harada) discloses a polyurethane hydrogel prepared from the reaction product of a polyisocyanate with a polyether which comprises a plurality of alkylene oxides, 50 to 90% by weight of which is ethylene oxide, added at random to a polyalcohol having at least two terminal hydroxyl groups. Harada requires that the prepolymers be liquid or pasty at room temperature in order to avoid having to liquify the prepolymer either by heating it or diluting it with a solvent. U.S. Pat. No. 4,381,332 (Fulmer et al.) discloses a polyurethane gel adhesive to form a nonwoven fabric, prepared from a prepolymer having molecular weight of at least 3000, made from an aliphatic polyisocyanate capped polyether polyol; up to 50% may be butylene oxide and propylene oxide. U.S. Pat. No. 3,719,050 (Asao) teaches a soil stabilization method in which a polyurethane prepolymer having terminal isocyanate groups is injected into the ground; the prepolymer may be diluted with water or may be reacted with water present in or flowing through the soil.
It can be seen that numerous combinations of molecular weights and prepolymer composition have been patented. Typically, prior hydrogel systems have required that the polyols and prepolymers be liquid or pasty at room temperatures to avoid having to melt the composition. This requirement places restraints on the composition of the polyols and prepolymers. As a rule, the prior art teaches copolymerization of propylene oxide or butylene oxide units sufficient to yield liquid polyols and prepolymers. However, inclusion of these monomer units also serves to decrease the hydrophilicity of the prepolymer. Additionally, low molecular weight prepolymers have been used to achieve this end.
In addition, biocompatibility is an increasingly desirable characteristic which would find numerous uses in the health care field if the appropriate properties can be obtained. However, many conventional hydrogels are not taught to be biocompatible.
Finally, prior art polyurethane hydrogels tend to adsorb proteins from solutions with which they are brought into contact. This is a particular problem in attempting to utilize conventional polymers for the preparation of controlled release membranes for delivery of proteinaceous drugs or medicaments.
These problems of biological incompatibility, the lack of hydrophilicity and the tendency to adsorb proteins, have raised significant concerns in the use of traditional controlled release membranes for the delivery of proteinaceous materials, in particular, for a family of proteins called growth factors. In general, proteinaceous drugs are active in minute quantities with disparate effects at different concentrations, and despite advances in recombinant technology, they remain expensive and available in small quantities. In addition, proteinaceous drugs are often not as stable as other medicaments. Prolonged storage may be accompanied by denaturation, degradation or adhesion of proteinaceous materials to the walls of the membranes with actual or effective loss in material or biological activity.
Consequently, there exists a need for polymers or hydrogels, and controlled-release membranes prepared therefrom, which possess improved biocompatibility and increased resistance to protein adsorption.